2.0 2012-05-31 13:03:32 -0600 2015-06-03 15:53:40 -0600 ECMDB01016 M2MDB000227 D-4'-Phosphopantothenate D-4'-Phosphopantothenate is a product of the phosphorylatation of Pantothenate by Pantothenate kinase. It is an intermediate in coenzyme A (CoA) biosynthesis pathway. Coenzyme A is a cofactor of ubiquitous occurrence in plants, bacteria, and animals. It is needed in a large number of enzymatic reactions central to intermediary metabolism, including the oxidation of fatty acids, carbohydrates, and amino acids. Only plants and microorganisms like E. coli are capable of synthesizing this compound de novo. (R)-4'-phosphopantothenate (R)-4'-phosphopantothenic acid 4'-P-Pantothenate 4'-P-Pantothenic acid 4'-Phosphopantothenate 4'-Phosphopantothenic acid 4'PPA D-4'-Phosphopantothenate D-4'-Phosphopantothenic acid C9H18NO8P 299.2149 299.077003069 3-{2-hydroxy-3-methyl-3-[(phosphonooxy)methyl]butanamido}propanoic acid 3-{2-hydroxy-3-methyl-3-[(phosphonooxy)methyl]butanamido}propanoic acid CC(C)(COP(O)(O)=O)C(O)C(=O)NCCC(O)=O InChI=1S/C9H18NO8P/c1-9(2,5-18-19(15,16)17)7(13)8(14)10-4-3-6(11)12/h7,13H,3-5H2,1-2H3,(H,10,14)(H,11,12)(H2,15,16,17) XHFVGHPGDLDEQO-UHFFFAOYSA-N Solid Cytosol logp -2.14 ALOGPS logs -1.55 ALOGPS solubility 8.51e+00 g/l ALOGPS logp -1.5 ChemAxon pka_strongest_acidic 1.79 ChemAxon pka_strongest_basic -3.8 ChemAxon iupac 3-{2-hydroxy-3-methyl-3-[(phosphonooxy)methyl]butanamido}propanoic acid ChemAxon average_mass 299.2149 ChemAxon mono_mass 299.077003069 ChemAxon smiles CC(C)(COP(O)(O)=O)C(O)C(=O)NCCC(O)=O ChemAxon formula C9H18NO8P ChemAxon inchi InChI=1S/C9H18NO8P/c1-9(2,5-18-19(15,16)17)7(13)8(14)10-4-3-6(11)12/h7,13H,3-5H2,1-2H3,(H,10,14)(H,11,12)(H2,15,16,17) ChemAxon inchikey XHFVGHPGDLDEQO-UHFFFAOYSA-N ChemAxon polar_surface_area 153.39 ChemAxon refractivity 62.38 ChemAxon polarizability 26.6 ChemAxon rotatable_bond_count 8 ChemAxon acceptor_count 7 ChemAxon donor_count 5 ChemAxon physiological_charge -3 ChemAxon formal_charge 0 ChemAxon Pantothenate and CoA biosynthesis The CoA biosynthesis requires compounds from two other pathways: aspartate metabolism and valine biosynthesis. It requires a Beta-Alanine and R-pantoate. The compound (R)-pantoate is generated in two reactions, as shown by the interaction of alpha-ketoisovaleric acid, 5,10 methylene-THF and water through a 3-methyl-2-oxobutanoate hydroxymethyltransferase resulting in a tetrahydrofolic acid and a 2-dehydropantoate. This compound interacts with hydrogen through a NADPH driven acetohydroxy acid isomeroreductase resulting in the release of NADP and R-pantoate. On the other hand L-aspartic acid interacts with a hydrogen ion and gets decarboxylated through an Aspartate 1- decarboxylase resulting in a carbon dioxide and a Beta-alanine. Beta-alanine and R-pantoate interact with an ATP driven pantothenate synthetase resulting in pyrophosphate, AMP, hydrogen ion and pantothenic acid. Pantothenic acid is phosphorylated through a ATP-driven pantothenate kinase resulting in a ADP, a hydrogen ion and D-4'-Phosphopantothenate. This compound interacts with a CTP and a L-cysteine resulting in a fused 4'-phosphopantothenoylcysteine decarboxylase and phosphopantothenoylcysteine synthetase resulting in a hydrogen ion, a pyrophosphate, a CMP and 4-phosphopantothenoylcysteine. The latter compound interacts with a hydrogen ion through a fused 4'-phosphopantothenoylcysteine decarboxylase and phosphopantothenoylcysteine synthetase resulting in a carbon dioxide release and a 4-phosphopantetheine. This compound interacts with an ATP, hydrogen ion and an phosphopantetheine adenylyltransferase resulting in a release of pyrophosphate, and dephospho-CoA. Dephospho-CoA reacts with an ATP driven dephospho-CoA kinase resulting in a ADP , a hydrogen ion and a Coenzyme A. . The latter is converted into (R)-4'-phosphopantothenate is two steps, involving a β-alanine ligase and a kinase. In most organsims the ligase acts before the kinase (EC 6.3.2.1, pantoate—β-alanine ligase (AMP-forming) followed by EC 2.7.1.33, pantothenate kinase, as described in phosphopantothenate biosynthesis I and phosphopantothenate biosynthesis II. However, in archaea the order is reversed, and EC 2.7.1.169, pantoate kinase acts before EC 6.3.2.36, 4-phosphopantoate—β-alanine ligase, as described in phosphopantothenate biosynthesis III. The kinases are feedback inhibited by CoA itself, accounting for the primary regulatory mechanism of CoA biosynthesis. The addition of L-cysteine to (R)-4'-phosphopantothenate, resulting in the formation of R-4'-phosphopantothenoyl-L-cysteine (PPC), is followed by decarboxylation of PPC to 4'-phosphopantetheine. The ultimate reaction is catalyzed by EC 2.7.1.24, dephospho-CoA kinase, which converts 4'-phosphopantetheine to CoA. All enzymes of this pathway are essential for growth. The reactions in the biosynthetic route towards CoA are identical in most organisms, although there are differences in the functionality of the involved enzymes. In plants every step is catalyzed by single monofunctional enzymes, whereas in bacteria and mammals bifunctional enzymes are often employed [Rubio06]. PW000828 ec00770 Metabolic beta-Alanine metabolism The Beta-Alanine Metabolism starts with a product of Aspartate metabolism. Aspartate is decarboxylated by aspartate 1-decarboxylase, releasing carbon dioxide and Beta-alanine. Beta alanine is then metabolized through a pantothenate synthetase resulting in Pantothenic acid undergoes phosphorylation through a ATP driven pantothenate kinase, resulting in D-4-phosphopantothenate. Pantothenate (vitamin B5) is the universal precursor for the synthesis of the 4'-phosphopantetheine moiety of coenzyme A and acyl carrier protein. Only plants and microorganismscan synthesize pantothenate de novo - animals require a dietary supplement. The enzymes of this pathway are therefore considered to be antimicrobial drug targets. PW000896 ec00410 Metabolic Metabolic pathways eco01100 phosphopantothenate biosynthesis I PANTO-PWY coenzyme A biosynthesis COA-PWY Specdb::CMs 3456 Specdb::CMs 37893 Specdb::NmrOneD 314561 Specdb::NmrOneD 314562 Specdb::NmrOneD 314563 Specdb::NmrOneD 314564 Specdb::NmrOneD 314565 Specdb::NmrOneD 314566 Specdb::NmrOneD 314567 Specdb::NmrOneD 314568 Specdb::NmrOneD 314569 Specdb::NmrOneD 314570 Specdb::NmrOneD 314571 Specdb::NmrOneD 314572 Specdb::NmrOneD 314573 Specdb::NmrOneD 314574 Specdb::NmrOneD 314575 Specdb::NmrOneD 314576 Specdb::NmrOneD 314577 Specdb::NmrOneD 314578 Specdb::NmrOneD 314579 Specdb::NmrOneD 314580 Specdb::MsMs 23426 Specdb::MsMs 23427 Specdb::MsMs 23428 Specdb::MsMs 30224 Specdb::MsMs 30225 Specdb::MsMs 30226 HMDB01016 41635 128 C03492 15905 4-P-PANTOTHENATE Keseler, I. M., Collado-Vides, J., Santos-Zavaleta, A., Peralta-Gil, M., Gama-Castro, S., Muniz-Rascado, L., Bonavides-Martinez, C., Paley, S., Krummenacker, M., Altman, T., Kaipa, P., Spaulding, A., Pacheco, J., Latendresse, M., Fulcher, C., Sarker, M., Shearer, A. G., Mackie, A., Paulsen, I., Gunsalus, R. P., Karp, P. D. (2011). "EcoCyc: a comprehensive database of Escherichia coli biology." Nucleic Acids Res 39:D583-D590. 21097882 Kanehisa, M., Goto, S., Sato, Y., Furumichi, M., Tanabe, M. (2012). "KEGG for integration and interpretation of large-scale molecular data sets." Nucleic Acids Res 40:D109-D114. 22080510 van der Werf, M. J., Overkamp, K. M., Muilwijk, B., Coulier, L., Hankemeier, T. (2007). "Microbial metabolomics: toward a platform with full metabolome coverage." Anal Biochem 370:17-25. 17765195 Winder, C. L., Dunn, W. B., Schuler, S., Broadhurst, D., Jarvis, R., Stephens, G. M., Goodacre, R. (2008). "Global metabolic profiling of Escherichia coli cultures: an evaluation of methods for quenching and extraction of intracellular metabolites." Anal Chem 80:2939-2948. 18331064 Pantothenate kinase P0A6I3 COAA_ECOLI coaA http://ecmdb.ca/proteins/P0A6I3.xml Coenzyme A biosynthesis bifunctional protein coaBC P0ABQ0 COABC_ECOLI coaBC http://ecmdb.ca/proteins/P0ABQ0.xml D-4'-Phosphopantothenate + Cytidine triphosphate + L-Cysteine > 4-Phosphopantothenoylcysteine + Cytidine monophosphate + Hydrogen ion + Pyrophosphate R04231 P-PANTOCYSLIG-RXN Adenosine triphosphate + Pantothenic acid <> D-4'-Phosphopantothenate + ADP + Hydrogen ion R03018 PANTOTHENATE-KIN-RXN Adenosine triphosphate + Pantothenic acid <> ADP + D-4'-Phosphopantothenate R03018 PANTOTHENATE-KIN-RXN Adenosine triphosphate + D-4'-Phosphopantothenate + L-Cysteine <> Adenosine monophosphate + Pyrophosphate + 4-Phosphopantothenoylcysteine R04230 Cytidine triphosphate + D-4'-Phosphopantothenate + L-Cysteine <> Cytidine monophosphate + Pyrophosphate + 4-Phosphopantothenoylcysteine R04231 Pantothenic acid + Adenosine triphosphate > Hydrogen ion + D-4'-Phosphopantothenate + ADP PANTOTHENATE-KIN-RXN Pantothenic acid + Adenosine triphosphate + Pantothenic acid > D-4'-Phosphopantothenate + Adenosine diphosphate + D-4'-Phosphopantothenate + ADP PW_R002990 Cytidine triphosphate + D-4'-Phosphopantothenate + L-Cysteine + D-4'-Phosphopantothenate > Cytidine monophosphate + Pyrophosphate + 4-Phosphopantothenoylcysteine + Cytidine monophosphate PW_R002991 Pantothenic acid + Adenosine triphosphate + Pantothenic acid > Adenosine diphosphate + Hydrogen ion + D-4'-Phosphopantothenate + ADP + D-4'-Phosphopantothenate PW_R003002 D-4'-Phosphopantothenate + Cytidine triphosphate + L-Cysteine + D-4'-Phosphopantothenate > Cytidine monophosphate + Pyrophosphate + Hydrogen ion + 4-Phosphopantothenoylcysteine + Cytidine monophosphate PW_R003003 D-4'-Phosphopantothenate + Cytidine triphosphate + L-Cysteine >4 4-Phosphopantothenoylcysteine + Cytidine monophosphate + Hydrogen ion + Pyrophosphate D-4'-Phosphopantothenate + Cytidine triphosphate + L-Cysteine >4 4-Phosphopantothenoylcysteine + Cytidine monophosphate + Hydrogen ion + Pyrophosphate